期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 196, 期 10, 页码 1255-1263出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201704-0769OC
关键词
transient receptor potential channels; ion channels; vagal afferent; cough; transient receptor potential vanilloid 1
资金
- National Institute for Health Research
- South Manchester Respiratory & Allergy Clinical Research Facility
- Northern Ireland Clinical Research Network (Respiratory Health)
- MRC [G0701918, MR/K020293/1] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre, MRC-Asthma UK Centre] Funding Source: researchfish
- Medical Research Council [MR/K020293/1, G0701918, G1000758, G1000758B] Funding Source: researchfish
Rationale: Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough. Objectives: XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. Methods: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes. Measurements and Main Results: XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 +/- 16.4) coughs; placebo, -1.8 +/- 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 +/- 16.9 coughs/h; placebo, 0.4 +/- 13.7 coughs/h; P = 0.41). Conclusions: XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough.
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